Figure 5.5 Comparing liposome-water to octanol-water partition coefficients of a series of uncharged substituted benzylalkylamines [387]. The membrane partitioning of the smaller members of the series (n = 0 ■■■ 3) is thought to be dominated by electrostatic and H-bonding effects (enthalpy-driven), whereas the partitioning of the larger members is thought to be directed by hydrophobic forces (entropy-driven) [387]. [Avdeef, A., Curr. Topics Med. Chem., 1, 277-351 (2001). Reproduced with permission from Bentham Science Publishers, Ltd.]

membrane partitioning does not change for n = 0-3 in the series. For n = 4-6 the octanol and membrane partition coefficients change at about the same rate. For longer-chain members of the series, the partitioning in both solvent systems expresses hydrophobicity (entropy-driven). However, for the short-chain members, various electrostatic and polar interactions play a role, and partitioning in the membrane system is not sensitive to the length of the chain (enthalpy-driven). It would be illuminating to subject this series to a precision microcalorimetric investigation.

When unrelated compounds are examined [149,162,385,386,429], exclusive of the phenols and the amines just considered, the variance of the relationship is considerably higher, but the general trend is evident, as seen in Fig. 5.6; the higher the octanol-water partition coefficient, the smaller is the 8 difference between membrane and octanol partitioning. The slope of the relationship is Fig. 5.6 is about twice that found for phenols. For molecules with log PNct between 2 and 4, 8 values are close to zero, indicating that the partition coefficients for many drug molecules are about the same in octanol as in phospholipid bilayers [149]. However, outside this interval, the differences can be substantial, as the next examples show. For hydrophilic molecules, the membrane partition coefficient is surprisingly high, in comparison to that of octanol. For example, acyclovir has log PN = —1.8 in octanol-water but +1.7 in liposome-water, indicating a 8 of +3.5 log units. Similar trends are found for other hydrophilic molecules, such as famotidine or zidovudine (Fig. 5.6). Atenolol and xamoterol also have notably high log PNmem values [433].

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